Acylated imidazolyl-O,N-acetals, their pharmaceutically acceptable salts and metal complexes

ABSTRACT

Acylated imidazolyl-O,N-acetals of the formula ##STR1## and their pharmaceutically acceptable salts and metal complexes wherein R is alkyl, alkenyl, alkinyl, cycloalkyl, halogenoalkyl, optionally substituted phenyl, optionally substituted phenoxyalkyl, alkylamino, dialkylamino or optionally substituted phenylamino; 
     X is halogen, alkyl, cycloalkyl, alkoxy, halogenoalkyl, alkylthio, alkoxycarbonyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylalkyl, amino, cyano or nitro; and 
     N is 0 or an integer of from 1 to 5; are useful as antimicrobial agents, particularly for their use in treating mycotic infectins in humans and animals.

The present invention relates to the use of new acylatedimidazolyl-O,N-acetals, pharmaceutically-acceptable, nontoxic saltsthereof and metal complexes thereof as antimicrobial agents,particularly as antimycotic agents. It is known thatimidazolyl-O,N-acetals, and especially1-imidazolyl-1-phenoxy-3,3-dimethylbutan-2-ols, exhibit good antimycoticactivity (see German OLS No. 2,333,355). However, the action of thosecompounds is not entirely satisfactory, particularly againstdermatophytes.

We have now discovered that acylated imidazolyl-O,N-acetals of theformula ##STR2## pharmaceutically acceptable salts thereof and metalcomplexes thereof, wherein

R is alkyl, especially of 1 to 18 carbon atoms, and particularly 1 to 12carbon atoms; alkenyl, especially of 2 to 4 carbon atoms; alkinyl,especially of 2 to 4 carbon atoms; cycloalkyl, especially of 5 to 7carbon atoms; halogenoalkyl, especially of 1 to 4 carbon atoms in thealkyl moiety and 1 to 5 halogen atoms; phenyl unsubstituted orsubstituted by halogen, cyano, nitro or alkyl, especially of 1 to 4carbon atoms; phenoxyalkyl, especially of 1 or 2 carbon atoms in thealkyl moiety, unsubstituted or nuclear-substituted by halogen, amino,cyano, nitro or alkyl of 1 to 4 carbon atoms; alkylamino, especiallylower alkylamino; dialkylamino, especially di-lower alkylamino; orphenylamino unsubstituted or nuclear-substituted by halogen, nitro orcyano;

X is halogen; alkyl, especially lower alkyl; cycloalkyl, especially of 5to 7 carbon atoms; alkoxy, especially of 1 to 4 carbon atoms;halogenoalkyl, especially of 1 to 4 carbon atoms in the alkyl moiety and1 to 5 halogen atoms; alkylthio, especially of 1 to 4 carbon atoms inthe alkyl moiety; alkoxycarbonyl, especially of 1 to 4 carbon atoms inthe alkoxy moiety; phenyl unsubstituted or substituted by halogen,amino, cyano, nitro or alkyl, especially of 1 or 2 carbon atoms; phenoxyunsubstituted or nuclear-substituted by halogen, amino, cyano, nitro oralkyl, especially of 1 or 2 carbon atoms; amino; cyano; or nitro; and

n is 0 or an integer from 1 to 5;

exhibit good antimicrobial properties and are particularly useful asantimycotics. In the above-referred-to formula, when n is an integerfrom 2 to 5 and therefore there is more than one X present in the phenylmoiety, the X's may be the same or different.

According to one embodiment of the present invention

R is alkyl of 1 to 8 carbon atoms; alkenyl of 2 to 4 carbon atoms;alkinyl of 2 to 4 carbon atoms; halogenoalkyl of 1 or 2 carbon atoms inthe alkyl moiety and 1 to 5 halogen atoms selected from the groupconsisting of fluorine or chlorine; cycloalkyl of 5 to 7 carbon atoms;phenyl unsubstituted or substituted by halogen, cyano, nitro or alkyl of1 or 2 carbon atoms; phenoxyalkyl of 1 or 2 carbon atoms in the alkylmoiety unsubstituted or nuclear-substituted by halogen, amino, cyano,nitro or alkyl of 1 or 2 carbon atoms; alkylamino of 1 to 4 carbon atomsin the alkyl moiety; dialkylamino of 1 to 4 carbon atoms in each alkylmoiety; or phenylamino unsubstituted or nuclear-substituted by halogen,nitro or cyano;

X is halogen; amino; cyano; nitro; alkyl of 1 to 4 carbon atoms;cycloalkyl of 5 to 7 carbon atoms; halogenoalkyl of 1 or 2 carbon atomsin the alkyl moiety and 1 to 5 halogen atoms selected from the groupconsisting of fluorine and chlorine; alkoxycarbonyl of 1 to 4 carbonatoms in the alkoxy moiety; alkoxy of 1 or 2 carbon atoms; alkylthio of1 or 2 carbon atoms; phenyl unsubstituted or substituted by halogen,amino, cyano, nitro or alkyl of 1 or 2 carbon atoms; phenoxyunsubstituted or substituted by halogen, amino, cyano, nitro or alkyl of1 or 2 carbon atoms; or phenylalkyl of 1 or 2 carbon atoms in the alkylmoiety unsubstituted or substituted in the alkyl portion byalkylcarbonyl of up to 3 carbon atoms in total and unsubstituted orsubstituted in the phenyl portion by halogen, nitro or cyano; and

n is 0 or an integer from 1 to 3.

According to another embodiment of the present invention

R is alkyl of 1 to 6 carbon atoms; alkenyl of 2 to 4 carbon atoms;alkinyl of 2 to 4 carbon atoms; halogenoalkyl of 1 or 2 carbon atoms inthe alkyl moiety and 1 to 5 halogen atoms selected from the groupconsisting of fluorine or chlorine; cyclohexyl; phenyl unsubstituted orsubstituted by halogen, cyano, nitro or alkyl of 1 or 2 carbon atoms;phenoxyalkyl of 1 or 2 carbon atoms in the akyl moiety unsubstituted ornuclear-substituted by halogen, amino, cyano, nitro or alkyl of 1 or 2carbon atoms; alkylamino of 1 or 2 carbon atoms in the alkyl moiety;dialkylamino of 1 to 4 carbon atoms in each alkyl moiety; or phenylaminounsubstituted or nuclear-substituted by halogen, nitro or cyano;

X is halogen; amino; cyano; nitro; alkyl of 1 to 4 carbon atoms;cyclohexyl; halogenoalkyl of 1 or 2 carbon atoms in the alkyl moiety and1 to 5 halogen atoms selected from the group consisting of fluorine andchlorine; alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy moiety;alkoxy of 1 or 2 carbon atoms; alkylthio of 1 or 2 carbon atoms; phenylunsubstituted or substituted by halogen, amino, cyano, nitro or alkyl of1 or 2 carbon atoms; phenoxy unsubstituted or nuclear-substituted byhalogen, amino, cyano, nitro or alkyl of 1 or 2 carbon atoms; orphenylalkyl of 1 or 2 carbon atoms in the alkyl moiety unsubstituted orsubstituted in the alkyl portion by alkylcarbonyl of up to 3 carbonatoms in total and unsubstituted in the phenyl portion or substituted inthe phenyl portion by halogen, nitro or cyano; and

n is 0 or an integer from 1 to 3.

According to another embodiment of the present invention

R is alkyl of 1 to 4 carbon atoms; alkenyl of 2 to 4 carbon atoms;alkinyl of 2 to 4 carbon atoms; cycloalkyl of 5 or 6 carbon atoms;phenyl unsubstituted or substituted by chlorine; phenoxyalkyl of 1 or 2carbon atoms in the alkyl moiety; alkylamino of 1 or 2 carbon atoms;dialkylamino of 1 or 2 carbon atoms; or phenylamino unsubstituted ornuclear-substituted by chlorine;

X is halogen; alkyl of 1 to 4 carbon atoms; cycloalkyl of 5 or 6 carbonatoms; trifluoromethyl; alkylthio of 1 or 2 carbon atoms; alkoxycarbonylof 1 or 2 carbon atoms in the alkoxy moiety; phenyl unsubstituted orsubstituted by halogen; phenoxy unsubstituted or substituted by halogen;phenylalkyl of 1 or 2 carbon atoms in the alkyl moiety; or nitro; and

n is 0 or an integer from 1 to 3.

According to another embodiment of the present invention

R is alkyl of 1 to 4 carbon atoms, allyl, cyclohexyl, phenylunsubstituted or substituted by chlorine, phenoxymethyl, alkylamino of 1or 2 carbon atoms, dimethylamino or chlorophenylamino;

X is chlorine, alkyl of 1 to 4 carbon atoms, cyclopentyl, cyclohexyl,trifluoromethyl, methylthio, alkoxycarbonyl of 1 or 2 carbon atoms inthe alkoxy moiety, phenyl unsubstituted or substituted by halogen,phenoxy unsubstituted or substituted by halogen, benzyl or nitro; and

n is 0 or an integer from 1 to 3.

According to another embodiment of the present invention

R is alkyl of 1 to 18 carbon atoms, halogenoalkyl of 1 to 4 carbon atomsin the alkyl moiety and 1 to 3 halogen atoms, alkylamino of 1 to 4carbon atoms in the alkyl portion or phenylamino unsubstituted ornuclear-substituted by chlorine;

X is halogen, cycloalkyl of 5 or 6 carbon atoms, phenyl or chlorophenyl;and

n is 0 or an integer from 1 to 3.

According to another embodiment of the present invention

R is methyl, butyl, heptadecyl, methylamino, tert.-butylamino,phenylamino or chlorophenylamino;

X is fluorine, chlorine, bromine, iodine, cyclohexyl, phenyl orchlorophenyl; and

n is 0 or an integer from 1 to 3.

The compounds of formula (I) have two asymmetric carbon atoms and can,therefore, be in the erythro or the threo form. Preferably, they areracemic.

The compounds of the present invention may be prepared by reacting animidazole derivative of the formula (II) ##STR3##

wherein X and n are as above defined, according to the four ProcessVariants A to D set forth below. The imidazole derivatives of theformula (II) are known from German OLS No. 2,333,355.

PROCESS VARIANT A

Imidazole derivatives of the formula (II) may be reacted with acidhalides according to procedures per se known; for example, in molaramounts in the presence of an inert organic solvent, such as ethylacetate, at temperatures of between 0° C. and 100° C. The compounds offormula (I) are obtained in the form of their hydrohalides and can beisolated as such by precipitating them utilizing an organic solvent,such as hexane, filtering them off and optionally purifying them byrecrystallization. The compounds of formula (I) can also be isolated inthe form of their free bases by adding aqueous sodium bicarbonatesolution to the reaction mixture and isolating the base according toprocedures per se known.

PROCESS VARIANT B

Imidazole derivatives of the formula (II) may be reacted with acidanhydrides according to procedures per se known; such as, for example,in molar amounts in the presence of an inert organic solvent, such asacetone or an excess of the acid anhydride, and in the presence of anacidic or basic catalyst, such as sodium acetate, at a temperature offrom 0° C. to 105° C., followed by isolation of the compounds of formula(I) according to procedures per se known.

PROCESS VARIANT C

Imidazole derivatives of the formula (II) may be reacted with ketenesaccording to procedures per se known; for example, in molar amounts inthe presence of an inert organic solvent, such as ethyl acetate, and inthe presence of an acidic or basic catalyst, such as sodium acetate, attemperatures of from -10° C. to +70° C., followed by isolation of thecompounds of formula (I) according to the procedures per se known.

PROCESS VARIANT D

Imidazole derivatives of the formula (II) may be reacted withisocyanates according to procedures per se known; for example, in molaramounts in the presence of an inert organic solvent, such as ethylacetate, and in the presence of a catalyst, such as triethylamine, attemperatures of from 0° C. to 100° C., followed by isolation of thecompounds of formula (I) according to procedures per se known.

The compounds of formula (I) form salts with pharmaceutically acceptableacids. These acids include the hydrogen halide acids such ashydrochloric acid and hydrobromic acid, especially hydrochloric acid,and phosphoric acid, nitric acid and monofunctional and bifunctionalcarboxylic acids and hydroxycarboxylic acids such as, for example,acetic acid, maleic acid, succinic acid, formaric acid, tartaric acid,citric acid, salicyclic acid, sorbic acid, lactic acid and1,5-naphthalene disulphonic acid.

The salts of compounds of the formula (I) can be obtained in a simplemanner by procedures per se known for forming salts, such as bydissolving the base in an ether, such as diethyl ether, and adding theappropriate acid, isolating the salt according to procedures per seknown, such as by filtering off, and, optionally, purifying the salt.

Compounds of the formula (I) may also be present in the form ofcomplexes with metal salts. Metals which may be mentioned for thesecomplexes are preferably metals of main groups II to IV and ofsub-groups I, II and IV to VIII of the periodic table, especiallycopper, zinc, manganese, magnesium, tin, iron and nickel. Suitable saltsinclude the pharmaceutically acceptable salts which are formed withacids such as those set forth above. Preferred acids include thehydrogen halide acids such as hydrochloric acid and hydrobromic acid,and phosphoric acid, nitric acid and sulphuric acid.

The metal complexes of the present invention can be obtained in a simplemanner by procedures per se known; for example, by dissolving the metalsalt in an alcohol, for example, ethanol, and adding the solution to thebase. Isolation is accomplished in a manner per se known; for example,by filtering off, and, optionally, purifying by recrystallization.

Representative compounds according to the present invention include thefollowing:

2-acetoxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(2-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(2,4,5-trichlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(4-nitrophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(2-cyclopentylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(3-trifluoromethylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(4-methylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(4-methoxycarbonylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(3-ethoxyphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(4-methylthiophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(4,4'-chlorophenylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(4-chloro-2-methylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(4-phenoxyphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(3,4-dimethylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(4,4'-iodobiphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-acetoxy-1-(4-benzylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-ethylcarbonyloxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane,

2-ethylcarbonyloxy-1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-ethylcarbonyloxy-1-(2-phenylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-isopropylcarbonyloxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane,

2-isopropylcarbonyloxy-1-(4-fluorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-tert.-butylcarbonyloxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane,

2-butylcarbonyloxy-1-(4-bromophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-propenylcarbonyloxy-1-(2,5-dichlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-allylcarbonyloxy-1-(4-tert.-butylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-propynylcarbonyloxy-1-(4-cyclohexylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-cyclohexylcarbonyloxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane,

2-phenylcarbonyloxy-1-(5-chloro-2-methylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-(4-chlorophenylcarbonyloxy)-1-(2-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-phenoxymethylcarbonyloxy-1-(4-phenylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-phenoxymethylcarbonyloxy-1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-ethylcarbamoyloxy-1-(2,4-dichlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-dimethylcarbamoyloxy-1-(4-nitrophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-methylcarbamoyloxy-1-(2,4,5-trichlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-methylcarbamoyloxy-1-(2-phenylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-methylcarbamoyloxy-1-(3,4-dimethylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-methylcarbamoyloxy-1-(2-methyl-5-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-methylcarbamoyloxy-1-(4-chloro-3,5-dimethylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane,

2-phenylcarbamoyloxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane, and

2-(4-chlorophenylcarbamoyloxy)-1-(4-phenylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane.

The compounds of formula (I), their pharmaceutically acceptable saltsand metal complexes display a broad antimycotic spectrum of activity,especially against dermatophytes and blastomyces and also biphase fungi,for example, against Candida species such as Candida albicans,Epidermophyton species such as Epidermophyton floccosum, Aspergillusspecies such as Aspergillus niger, Trichophyton species such asTrichophyton mentagrophytes, Microsporon such as Microsporon felineum,and Penicillium species such as Penicillium commune.

The compounds of the present invention, their pharmaceuticallyacceptable salts and metal complexes are thus particularly useful fortreating dermatomycoses, systemic mycoses caused by Trichophytonmentagrophytes and other Trichophyton species, Microsporon species,Epidermophyton floccosum, blastomyces and biphase fungi, as well asmolds, in humans and in treating dermatomycoses, systemic mycoses andespecially those caused by the abovementioned pathogens in animals.

The pharmaceutical compositions of the present invention contain a majoror minor amount, e.g., 0.1% to 99.5%, preferably 0.5% to 90% of at leastone active compound as above defined in combination with apharmaceutically acceptable, nontoxic, inert diluent or carrier, thecarrier comprising one or more solid, semi-solid or liquid diluent,filler and formulation adjuvant which is nontoxic, inert andpharmaceutically acceptable. Such pharmaceutical compositions arepreferably in dosage unit form; i.e., physically discrete unitscontaining a predetermined amount of the drug corresponding to afraction or multiple of the dose which is calculated to produce thedesired therapeutic response. The dosage units can contain one, two,three, four or more single doses, or, alternatively, one half, third orfourth of a single dose. A single dose preferably contains an amountsufficient to produce the desired therapeutic effect upon administrationat one application of one or more dosage units according to apredetermined dosage regimen, usually a whole, half, third or quarter ofthe daily dosage administered once, twice, three or four times a day.Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the dosage will be from10 mg/kg to 300 mg/kg of body weight per day and preferably from 50mg/kg to 200 mg/kg of body weight per day. In some instances asufficient therapeutic effect can be obtained at a lower dose, while inothers a larger dose will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as, for example, starch, lactose, sucrose, glucoseor mannitol. Sweetening, flavoring, preservative, dispersing andcoloring agents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as described aboveand, optionally, with a binder such as carboxymethyl cellulose, analginate, gelatin or polyvinyl pyrrolidone, a solution retardant such asparaffin, a resorption accelerator such as a quaternary salt and/or anabsorption agent such as bentonite, kaolin or dicalcium phosphate. Thepowder mixture can be granulated by wetting with a binder such as syrup,starch paste, acacia mucilage or solutions of cellulosic or polymericmaterials and forcing through a screen. An an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet-formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free-flowing, inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a nontoxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a nontoxicvehicle. Solubilizers and emulsifiers, such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like, can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as, for example, by coating or embedding particulatematerial in polymers, wax, or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Nontoxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low-melting, water-soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher esters as, forexample, myristyl palmitate, or mixtures thereof.

Topical administration can be effected utilizing solid dosage unit formssuch as powders or liquid or semi-liquid dosage unit forms such assolutions, suspensions, ointments, pastes, creams and gels. The powdersare formulated utilizing such carriers as talc, bentonite, silicic acid,polyamide powder and the like. Liquid and semi-liquid formulations canutilize such carriers, in addition to those described above, aspolyethylene glycol, vegetable and mineral oils, alcohols such asisopropanol, and the like. Other excipients such as emulsifiers,preservatives, colorants, perfumes and the like can also be present.Formulations can also be administered as an aerosol, utilizing the usualpropellants such as the chlorofluorohydrocarbons.

While the routes of administration include oral, parenteral (i.e.,intramuscular, intraperitoneal and intravenous), rectal and topical,parenteral administration, especially intravenous, is particularlypreferred.

Examples A and B, set forth below, illustrate the antimycotic activityof the compounds of the present invention.

EXAMPLE A Antimycotic in vitro activity

Description of the experiment:

The in vitro tests were carried out in a series dilution test using germinocula with an average of 5×10⁴ germs/ml of substrate. The nutrientmedium used was (a) for dermatophytes and molds: Sabouraud's milieud'epreuve and (b) for yeasts: meat extract/glucose broth.

The incubation temperature was 28° C. and the incubation time was 24 to96 hours.

                                      Table A                                     __________________________________________________________________________    Antimycotic in vitro activity                                                                               MIC values in γ/ml of nutrient medium                                   with                                                                          Trichophyton                                                                          Microsporum                                                                          Penicillium                                                                         Aspergillus                                                                         Candida              Active Compound               mentagrophytes                                                                        felinum                                                                              commune                                                                             niger albicans             __________________________________________________________________________     ##STR4##                     64      --     >64   --    32                   (known)                                                                        ##STR5##                     32      --     >64   --    64                   (known)                                                                        ##STR6##                     32      >64    >64   >64   32                   (known)                                                                        ##STR7##                  (2)                                                                               4      32     32    64    32                    ##STR8##                  (4)                                                                              <1       8      8    <1    64                    ##STR9##                  (5)                                                                               4      32     32    64    64                    ##STR10##                 (13)                                                                              4      32     64    64    32                    ##STR11##                 (9)                                                                              <1      32     64    64    32                    ##STR12##                 (6)                                                                               8      --     32    --    64                   __________________________________________________________________________

example b antimycotic in vivo activity on candidosis in mice

Description of the experiment:

Mice of the SPF-CF₁ type were infected intravenously with 1-2×10⁶logarithmically-growing Candida cells, which were suspended inphysiological sodium chloride solution. One hour before and seven hoursafter the infection the aninals were treated orally with, in each case,100 mg of the formulations per kg of body weight.

Untreated animals died of the infection 3 to 6 days after infection. Thesurvival rate on the 6th day after infection was about 5% in the case ofthe untreated control animals.

                  Table B                                                         ______________________________________                                        Antimycotic in vivo activity on candidosis in mice                            Active compound             Action                                            ______________________________________                                         ##STR13##                      +                                             (known)                                                                        ##STR14##                      NA                                            (known)                                                                        ##STR15##               (2)    ++++                                           ##STR16##               (5)    ++                                             ##STR17##               (1)    ++                                             ##STR18##               (9)    ++++                                           ##STR19##               (3)    +++                                            ##STR20##               (13)   +                                             ______________________________________                                         ++++ = good action = ≧80% survivors on the 6th day after infection      +++ = action = ≧60% survivors on the 6th day after infection            ++ = weak action = ≧40% survivors on the 6th day after infection        + = trace action = <40% survivors on 6th day after infection               NA = no action                                                           

The following non-limitative examples more particularly illustrate thepresent invention:

EXAMPLE 1 ##STR21## (Process variant A)

8.0 g (0.1 mol) of acetyl chloride are added to 20.6 g (0.1 mol) of1-imidazol-1-yl-1-phenoxy-3,3-dimethyl-butan-2-ol in 100 ml of ethylacetate at room temperature. The mixture is then heated under reflux for4 hours. It is allowed to cool and concentrated by distilling off thesolvent in vacuo. The residue is taken up in benzene and the solution iswashed with aqueous sodium bicarbonate solution and dried over sodiumsulphate. The solvent is distilled off under a water pump vacuum and theresidue is recrystallized from petroleum ether. 20.6 g (45% of theory)of 2-acetoxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane are obtainedas a mixture of isomers with a melting point of 114°-121° C.

Starting material ##STR22##

25.8 g (0.1 mol) of 1-imidazol-1-yl-1-phenoxy-3,3-dimethyl-butan-2-oneare dissolved in 250 ml of methanol and 5.9 g (0.15 mol) of sodiumborohydride are introduced in portions into this solution, at 5° to 10°C., while stirring and with reflux cooling. After stirring for 15 hoursat room temperature, 20 ml of concentrated hydrochloric acid are addedand the reaction mixture is stirred for a further 15 hours at roomtemperature and poured into 300 ml of saturated sodium bicarbonatesolution. The mixture is extracted with twice 100 ml of methylenechloride, the organic phase is washed with twice 100 ml of water anddried over sodium sulphate and the solvent is distilled off under awater pump vacuum. The residue is ground with 30 ml of petroleum ether.21.6 g (83% of theory) of1-imidazol-1-yl-1-phenoxy-3,3-dimethyl-butan-2-ol are obtained as amixture of isomers with a melting point of 99°-105° C.

EXAMPLE 2 ##STR23## (Process variant B)

8.0 g (0.027 mol) of1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butan-2-ol are heatedin 40 ml of acetic anhydride with 0.15 g of sodium acetate for 10 hoursat 100° C. The solution is then cooled and stirred into 400 ml of icewater, the temperature being kept at 20°-25° C. The mixture is left tostand overnight. A smeary crystalline mass precipitates out and is takenup in chloroform. The chloroform solution is washed several times withwater and sodium bicarbonate solution, dried over sodium sulphate andconcentrated in vacuo by distilling off the solvent. The crystallineresidue is boiled up in petroleum ether and the product is filtered offcold and dried. 4.5 g (49% of theory) of2-acetoxy-1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane areobtained as a mixture of isomers with a melting point of 81°-91° C.

EXAMPLES 3-23

The compounds below set forth in tabular form are produced in a manneranalogous to that described in Examples 1 and 2.

General formula:

    __________________________________________________________________________     ##STR24##                                                                                                   Melting point (°C.)                                                    as a mixture of                                Example No.                                                                          X.sub.n     R           isomers                                        __________________________________________________________________________    3      4-F         CH.sub.3    144-53                                                 ##STR25##  CH.sub.3    117-24                                         5      4-Br        CH.sub.3     78-89                                         6                                                                                     ##STR26##  CH.sub.3                                                                                   ##STR27##                                     7                                                                                     ##STR28##  CH.sub.3                                                                                   ##STR29##                                     8                                                                                     ##STR30##  CH.sub.3    250-56, decomposition                                                          ##STR31##                                     9                                                                                     ##STR32##  CH.sub.3    118-29                                         10                                                                                    ##STR33##  CH.sub.3     92-97                                         11     3-Br        CH.sub.3                                                                                   ##STR34##                                     12                                                                                    ##STR35##  CH.sub.3                                                                                   ##STR36##                                     13     4-J         CH.sub.3    100-06                                         14     2-F         CH.sub.3     91-102                                        15     4-Cl        CH.sub.2 Cl 194 (x HCl)                                    16     4-Cl        CHCl.sub.2  105-07 (x HCl)                                 17     4-Cl        CH.sub.2CH(CH.sub.3).sub.2                                                                 ##STR37##                                     18     4-Cl        (CH.sub.2).sub.16 CH.sub.3                                                                 ##STR38##                                     19     4-Cl        NHC(CH.sub.3).sub.3                                                                       111-15                                         20     4-Cl        NHCH.sub.3  183-190                                        21     4-Cl                                                                                       ##STR39##  170-173                                        22     4-Cl                                                                                       ##STR40##  177-185                                        23                                                                                    ##STR41##  CH.sub.3    219-221 (x HCl)                                24     4-O         NHCH.sub.3  187                                            25     4-O         NHC.sub.3 H.sub.7                                                                         124-138                                        26     4-O         NHC.sub.2 H.sub.5                                                                          98-120                                        27     4-O         NHC.sub.4 H.sub.9                                                                         118-127                                        __________________________________________________________________________

what is claimed is:
 1. A pharmaceutical composition for treating mycosesin humans and animals which comprises an antimycotically effectiveamount of a compound of the formula ##STR42## or a pharmaceuticallyacceptable, nontoxic salt or metal complex thereof, whereinR is alkyl of1 to 18 carbon atoms; alkenyl of 2 to 4 carbon atoms; alkinyl of 2 to 4carbon atoms; cycloalkyl of 5 to 7 carbon atoms; halogenoalkyl of 1 to 4carbon atoms in the alkyl moiety and 1 to 5 halogen atoms; orphenoxyalkyl unsubstituted or nuclear-substituted by halogen, amino,cyano, nitro or alkyl of 1 to 4 carbon atoms; X is halogen; lower alkyl;cycloalkyl of 5 to 7 carbon atoms; alkoxy of 1 to 4 carbon atoms;halogenoalkyl of 1 to 4 carbon atoms in the alkyl moiety and 1 to 5halogen atoms; alkylthio of 1 to 4 carbon atoms; alkoxycarbonyl of 1 to4 carbon atoms in the alkoxy moiety; phenyl unsubstituted or substitutedby halo, amino, cyano, nitro or alkyl of 1 to 4 carbon atoms; phenoxyunsubstituted or nuclear-substituted by halo, amino, cyano, nitro oralkyl of 1 to 4 carbon atoms; amino, cyano; or nitro; and n is 0 or aninteger from 1 to 5; in combination with a pharmaceutically acceptable,non-toxic carrier suitable for administration to humans and animals. 2.A pharmaceutical composition according to claim 1 whereinR is alkyl of 1to 8 carbon atoms; alkenyl of 2 to 4 carbon atoms; alkinyl of 2 to 4carbon atoms; halogenoalkyl of 1 to 2 carbon atoms in the alkyl moietyand 1 to 5 halogen atoms selected from the group consisting of fluorineand chlorine; cycloalkyl of 5 to 7 carbon atoms; or phenoxyalkyl of 1 to2 carbon atoms in the alkyl moiety unsubstituted or nuclear-substitutedby halogen, amino, cyano, nitro or alkyl of 1 or 2 carbon atoms; X ishalogen; amino; cyano; nitro; alkyl of 1 to 4 carbon atoms; cycloalkylof 5 to 7 carbon atoms; halogenoalkyl of 1 or 2 carbon atoms in thealkyl moiety and 1 to 5 halogen atoms selected from the group consistingof fluorine and chlorine; alkoxycarbonyl of 1 to 4 carbon atoms in thealkoxy moiety; alkoxy of 1 to 2 carbon atoms; alkylthio of 1 or 2 carbonatoms; phenyl unsubstituted or substituted by halogen, amino, cyano,nitro or alkyl of 1 or 2 carbon atoms; phenoxy unsubstituted orsubstituted by halogen, amino, cyano, nitro or alkyl of 1 or 2 carbonatoms; or phenylalkyl of 1 or 2 carbon atoms in the alkyl moietyunsubstituted or substituted in the alkyl portion by alkylcarbonyl of upto 3 carbon atoms in total and unsubstituted or substituted in thephenyl portion by halogen, nitro or cyano; and n is 0 or an integer from1 to
 3. 3. A pharmaceutical composition according to claim 1 whereinR isalkyl of 1 to 6 carbon atoms; alkenyl of 2 to 4 carbon atoms; alkinyl of2 to 4 carbon atoms; halogenoalkyl of 1 or 2 carbon atoms in the alkylmoiety and 1 to 5 halogen atoms selected from the group consisting offluorine and chlorine; cyclohexyl; or phenoxyalkyl of 1 or 2 carbonatoms in the alkyl moiety unsubstituted or nuclear-substituted byhalogen, amino, cyano, nitro or alkyl of 1 or 2 carbon atoms; X ishalogen; amino; cyano; nitro; alkyl of 1 to 4 carbon atoms; cyclohexyl;halogenoalkyl of 1 or 2 carbon atoms in the alkyl moiety and 1 to 5halogen atoms selected from the group consisting of fluorine andchlorine; alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy moiety;alkoxy of 1 or 2 carbon atoms; alkylthio of 1 or 2 carbon atoms; phenylunsubstituted or substituted by halogen, amino, cyano, nitro or alkyl of1 or 2 carbon atoms; phenoxy unsubstituted or nuclear-substituted byhalogen, amino, cyano, nitro or alkyl of 1 or 2 carbon atoms; orphenylalkyl of 1 or 2 carbon atoms in the alkyl moiety unsubstituted orsubstituted in the alkyl portion by alkylcarbonyl of up to 3 carbonatoms in total and unsubstituted in the phenyl portion or substituted inthe phenyl portion by halogen, nitro or cyano; and n is 0 or an integerfrom 1 to
 3. 4. A pharmaceutical composition according to claim 1whereinR is alkyl of 1 to 4 carbon atoms; alkenyl of 2 to 4 carbonatoms; alkinyl of 2 to 4 carbon atoms; cycloalkyl of 5 or 6 carbonatoms; or phenoxyalkyl of 1 or 2 carbon atoms in the alkyl moiety; X ishalogen; alkyl of 1 to 4 carbon atoms; cycloalkyl of 5 or 6 carbonatoms; trifluoromethyl; alkylthio of 1 or 2 carbon atoms; alkoxycarbonylof 1 or 2 carbon atoms in the alkoxy moiety; phenyl unsubstituted orsubstituted by halogen; phenoxy unsubstituted or substituted by halogen;phenylalkyl of 1 or 2 carbon atoms in the alkyl moiety; or nitro; and nis 0 or an integer from 1 to
 3. 5. A pharmaceutical compositionaccording to claim 1 whereinR is alkyl of 1 to 4 carbon atoms, allyl,cyclohexyl, or phenoxymethyl; X is chlorine, alkyl of 1 to 4 carbonatoms, cyclopentyl, cyclohexyl, trifluoromethyl, methylthio,alkoxycarbonyl of 1 or 2 carbon atoms in the alkoxy moiety, phenylunsubstituted or substituted by halogen, phenoxy unsubstituted orsubstituted by halogen, benzyl or nitro; and n is 0 or an integer from 1to
 3. 6. A pharmaceutical composition according to claim 1 wherein thecompound is in the form of a pharmaceutically acceptable salt selectedfrom the group consisting of the hydrochloride, hydrobromide, phosphate,nitrate, acetate, maleate, succinate, fumarate, tartrate, citrate,salicylate, sorbate, lactate and 1,5-naphthalene disulfonate.
 7. Apharmaceutical composition according to claim 1 wherein the compound isin the form of a metal complex wherein the metal is copper, zinc,manganese, magnesium, tin, iron or nickel.
 8. A pharmaceuticalcomposition according to claim 1 whereinR is alkyl of 1 to 18 carbonatoms or halogenoalkyl of 1 to 4 carbon atoms in the alkyl moiety and 1to 3 halogen atoms; X is halogen, cycloalkyl of 5 or 6 carbon atoms,phenyl or chlorophenyl; and n is 0 or an integer from 1 to
 3. 9. Apharmaceutical composition according to claim 1 whereinR is methyl,butyl or heptadecyl; X is fluorine, chlorine, bromine, iodine,cyclohexyl, phenyl or chlorophenyl; and n is 0 or an integer from 1 to3.
 10. A pharmaceutical composition according to claim 1 wherein thecompound is in racemic form.
 11. A pharmaceutical composition accordingto claim 1 wherein the compound is in erythro form.
 12. A pharmaceuticalcomposition according to claim 1 wherein the compound is in threo form.13. A pharmaceutical composition according to claim 1 wherein thecompound is ##STR43##
 14. A pharmaceutical composition according toclaim 1 wherein the compound is ##STR44##
 15. A pharmaceuticalcomposition according to claim 1 wherein R is methyl, X is 4-fluorineand n is
 1. 16. A pharmaceutical composition according to claim 1wherein R is methyl, X is 4-phenyl and n is
 1. 17. A pharmaceuticalcomposition according to claim 1 wherein R is methyl, X is 4-bromine andn is
 1. 18. A pharmaceutical composition according to claim 1 wherein Ris methyl, X is 4-cyclohexyl and n is
 1. 19. A pharmaceuticalcomposition according to claim 1 wherein R is methyl, X is 2-phenyl andn is
 1. 20. A pharmaceutical composition according to claim 1 wherein Ris methyl, X is 2-cyclohexyl and n is
 1. 21. A pharmaceuticalcomposition according to claim 1 wherein R is methyl, X is4-parachlorophenyl and n is
 1. 22. A pharmaceutical compositionaccording to claim 1 wherein R is methyl, n is 2, one X is 2-chlorineand the other X is 4-phenyl.
 23. A pharmaceutical composition accordingto claim 1 wherein R is methyl, X is 3-bromine and n is
 1. 24. Apharmaceutical composition according to claim 1 wherein R is methyl, nis 3, one X is 2-chlorine, the second X is 6-chlorine and the third X is4-phenyl.
 25. A pharmaceutical composition according to claim 1 whereinR is methyl, X is 4-iodine and n is
 1. 26. A pharmaceutical compositionaccording to claim 1 wherein R is methyl, X is 2-fluorine and n is 1.27. A pharmaceutical composition according to claim 1 wherein R ischloromethyl, X is 4-chlorine and n is
 1. 28. A pharmaceuticalcomposition according to claim 1 wherein R is dichloromethyl, X is4-chlorine and n is
 1. 29. A pharmaceutical composition according toclaim 1 wherein R is isobutyl, X is 4-chlorine and n is
 1. 30. Apharmaceutical composition according to claim 1 wherein R is heptadecyl,X is 4-chlorine and n is
 1. 31. A pharmaceutical composition accordingto claim 1 wherein R is methyl, n is 2 and one X is 2-chlorine and theother X is 4-chlorine.
 32. A method for treating mycoses in humans andanimals which comprises administering to a human or animal in needthereof an antimycotically effective amount of a compound of the formula##STR45## or a pharmaceutically acceptable, nontoxic salt or metalcomplex thereof, whereinR is alkyl of 1 to 18 carbon atoms; alkenyl of 2to 4 carbon atoms; alkinyl of 2 to 4 carbon atoms; cycloalkyl of 5 to 7carbon atoms; halogenalkyl of 1 to 4 carbon atoms in the alkyl moietyand 1 to 5 halogen atoms; or phenoxyalkyl unsubstituted ornuclear-substituted by halogen, amino, cyano, nitro or alkyl of 1 to 4carbon atoms; X is halogen; lower alkyl; cycloalkyl of 5 to 7 carbonatoms; alkoxy of 1 to 4 carbon atoms; halogenoalkyl of 1 to 4 carbonatoms in the alkyl moiety and 1 to 5 halogen atoms; alkylthio of 1 to 4carbon atoms; alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxymoiety; phenyl unsubstituted or substituted by halo, amino, cyano, nitroor alkyl of 1 to 4 carbon atoms; phenoxy unsubstituted ornuclear-substituted by halo, amino, cyano, nitro or alkyl of 1 to 4carbon atoms; amino; cyano; or nitro; and n is 0 or an integer from 1 to5; in combination with a pharmaceutically acceptable, non-toxic carriersuitable for administration to humans and animals.
 33. A methodaccording to claim 32 whereinR is alkyl of 1 to 8 carbon atoms; alkenylof 2 to 4 carbon atoms; alkinyl of 2 to 4 carbon atoms; halogenoalkyl of1 or 2 carbon atoms in the alkyl moiety and 1 to 5 halogen atomsselected from the group consisting of fluorine and chlorine; cycloalkylof 5 to 7 carbon atoms; or phenoxyalkyl of 1 or 2 carbon atoms in thealkyl moiety unsubstituted or nuclear-substituted by halogen, amino,cyano, nitro or alkyl of 1 or 2 carbon atoms; X is halogen; amino;cyano; nitro; alkyl of 1 to 4 carbon atoms; cycloalkyl of 5 to 7 carbonatoms; halogenoalkyl of 1 or 2 carbon atoms in the alkyl moiety and 1 to5 halogen atoms selected from the group consisting of fluorine andchlorine; alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy moiety;alkoxy of 1 or 2 carbon atoms; alkylthio of 1 or 2 carbon atoms; phenylunsubstituted or substituted by halogen, amino, cyano, nitro or alkyl of1 or 2 carbon atoms; phenoxy unsubstituted or substituted by halogen,amino, cyano, nitro or alkyl of 1 or 2 carbon atoms; or phenylalkyl of 1or 2 carbon atoms in the alkyl moiety unsubstituted or substituted inthe alkyl portion by alkylcarbonyl of up to 3 carbon atoms in total andunsubstituted or substituted in the phenyl portion by halogen, nitro orcyano; and n is 0 or an integer from 1 to
 3. 34. A method according toclaim 32 whereinR is alkyl of 1 to 6 carbon atoms; alkenyl of 2 to 4carbon atoms; halogenoalkyl of 1 or 2 carbon atoms in the alkyl moietyand 1 to 5 halogen atoms selected from the group consisting of fluorineand chlorine; cyclohexyl; or phenoxyalkyl of 1 or 2 carbon atoms in thealkyl moiety unsubstituted or nuclear-substituted by halogen, amino,cyano, nitro or alkyl of 1 or 2 carbon atoms; X is halogen; amino;cyano; nitro; alkyl of 1 to 4 carbon atoms; cyclohexyl; halogenoalkyl of1 or 2 carbon atoms in the alkyl moiety and 1 to 5 halogen atomsselected from the group consisting of fluorine and chlorine;alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy moiety; alkoxy of 1or 2 carbon atoms; alkylthio of 1 or 2 carbon atoms; phenylunsubstituted or substituted by halogen, amino, cyano, nitro or alkyl of1 or 2 carbon atoms; phenoxy unsubstituted or nuclear-substituted byhalogen, amino, cyano, nitro or alkyl of 1 or 2 carbon atoms; orphenylalkyl of 1 or 2 carbon atoms in the alkyl moiety unsubstituted orsubstituted in the alkyl portion by alkylcarbonyl of up to 3 carbonatoms in total and unsubstituted in the phenyl portion or byalkylcarbonyl of up to 3 carbon atoms in total and unsubstituted orsubstituted in the phenyl portion by halogen, nitro or cyano; and n is 0or an integer from 1 to
 3. 35. A method according to claim 32 whereinRis alkyl of 1 to 4 carbon atoms; alkenyl of 2 to 4 carbon atoms; alkinylof 2 to 4 carbon atoms; cycloalkyl of 5 or 6 carbon atoms; orphenoxyalkyl of 1 or 2 carbon atoms in the alkyl moiety; X is halogen,alkyl of 1 to 4 carbon atoms; cycloalkyl of 5 or 6 carbon atoms;trifluoromethyl; alkylthio of 1 or 2 carbon atoms; alkoxycarbonyl of 1or 2 carbon atoms in the alkoxy moiety; phenyl unsubstituted orsubstituted by halogen; phenoxy unsubstituted or substituted by halogen;phenylalkyl of 1 or 2 carbon atoms in the alkyl moiety; or nitro; and nis 0 or an integer from 1 to
 3. 36. A method according to claim 32whereinR is alkyl of 1 to 4 carbon atoms, allyl, cyclohexyl, orphenoxymethyl; X is chlorine, alkyl of 1 to 4 carbon atoms, cyclopentyl,cyclohexyl, trifluoromethyl, methylthio, alkoxycarbonyl of 1 or 2 carbonatoms in the alkoxy moiety, phenyl unsubstituted or substituted byhalogen, phenoxy unsubstituted or substituted by halogen, benzyl ornitro; and n is 0 or an integer from 1 to
 3. 37. A method according toclaim 32 wherein the compound is in the form of a pharmaceuticallyacceptable salt selected from the group consisting of the hydrochloride,hydrobromide, phosphate, nitrate, acetate, maleate, succinate, fumarate,tartrate, citrate, salicylate, sorbate, lactate and 1,5-naphthalenedisulfonate.
 38. A method according to claim 32 wherein the compound isin the form of a metal complex wherein the metal is copper, zinc,manganese, magnesium, tin, iron or nickel.
 39. A method according toclaim 32 whereinR is alkyl of 1 to 18 carbon atoms or halogenoalkyl of 1to 4 carbon atoms in the alkyl moiety and 1 to 3 halogen atoms; X ishalogen, cycloalkyl of 5 or 6 carbon atoms, phenyl or chlorophenyl; andn is 0 or an integer from 1 to
 3. 40. A method according to claim 32whereinR is methyl, butyl or heptadecyl; X is fluorine, chlorine,bromine, iodine, cyclohexyl, phenyl or chlorophenyl; and n is 0 or aninteger from 1 to
 3. 41. A method according to claim 32 wherein thecompound is in racemic form.
 42. A method according to claim 32 whereinthe compound is in erythro form.
 43. A method according to claim 32wherein the compound is in threo form.
 44. A method according to claim32 wherein the compound is ##STR46##
 45. A method according to claim 32wherein the compound is ##STR47##
 46. A method according to claim 32wherein R is methyl, X is 4-fluorine and n is
 1. 47. A method accordingto claim 32 wherein R is methyl, X is 4-phenyl and n is
 1. 48. A methodaccording to claim 32 wherein R is methyl, X is 4-bromine and n is 1.49. A method according to claim 32 wherein R is methyl, X is4-cyclohexyl and n is
 1. 50. A method according to claim 32 wherein R ismethyl, X is 2-phenyl and n is
 1. 51. A method according to claim 32wherein R is methyl, X is 2-cyclohexyl and n is
 1. 52. A methodaccording to claim 33 wherein R is methyl, X is 4-parachlorophenyl and nis
 1. 53. A method according to claim 32 wherein R is methyl, n is 2,one X is 2-chlorine and the other X is 4-phenyl.
 54. A method accordingto claim 32 wherein R is methyl, X is 3-bromine and n is
 1. 55. A methodaccording to claim 32 wherein R is methyl, n is 3, one X is 2-chlorine,the second X is 6-chlorine and the third X is 4-phenyl.
 56. A methodaccording to claim 32 wherein R is methyl, X is 4-iodine and n is
 1. 57.A method according to claim 32 wherein R is methyl, X is 2-fluorine andn is
 1. 58. A method according to claim 32 wherein R is chloromethyl, Xis 4-chlorine and n is
 1. 59. A method according to claim 32 wherein Ris dichloromethyl, X is 4-chlorine and n is
 1. 60. A method according toclaim 32 wherein R is isobutyl, X is 4-chlorine and n is
 1. 61. A methodaccording to claim 32 wherein R is heptadecyl, X is 4-chlorine and nis
 1. 62. A method according to claim 32 wherein R is methyl, n is 2 andone X is 2-chlorine and the other X is 4-chlorine.
 63. A pharmaceuticalcomposition according to claim 1 in parenteral administration form. 64.A pharmaceutical composition according to claim 1 in intravenousadministration form.
 65. A method according to claim 32 wherein theadministration is parenteral.
 66. A method according to claim 32 whereinthe administration is intravenous.